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Salvage Chemotherapy for AML
Abstract & Commentary
By Andrew S. Artz, MD, MS, Hematology/Immunology Unit, National Institute on Aging, NIH. Dr. Artz reports no financial relationships relevant to this field of study.
Synopsis: The optimal standard salvage therapy for relapsed or refractory AML remains undetermined. The authors retrospectively compared two regimens at a single institution: CLAG (cladribine, high-dose cytarabine, and G-CSF) with MEC (mitoxantrone, etoposide, and cytarabine). These observational data without adjustment suggest CLAG may be superior to MEC. Nevertheless, outcomes for relapsed or refractory AML remain poor and clinical trials should be entertained when available.
Source: Price SL, et al. Salvage chemotherapy regimens for acute myeloid leukemia: Is one better? Efficacy comparison between CLAG and MEC regimens. Leuk Res 2011;35:301-304.
Initial therapy for acute myeloid leukemia (AML) employing cytarabine and an anthracycline (aka, "7 + 3") has remained relatively static for several decades, although recent studies demonstrate the value of higher daunorubicin dosing.1 Complete remission (CR) rates vary from 50%-80%, but most patients eventually succumb to relapse. Adverse prognostic markers at the time of relapse include shorter duration of first CR, higher risk initial karyotype, older age, and prior hematopoietic cell transplantation.2 As expected, outcomes after second salvage are dismal, with median survival of 1.5 months.3
As opposed to initial induction therapy, numerous drugs and combinations have been used for relapse without any standard emerging. For remission duration less than 6–12 months, responses range from 20% to 40%. Response rates for late remission are nearly similar to initial response rates, but overall survival remains poor. In appropriate candidates who achieve remission, an allogeneic hematopoietic cell transplant should be pursued.
In this study, the authors retrospectively compared mitoxantrone, etoposide, and cytarabine (MEC) to cladribine, high-dose cytarabine, and G-CSF (CLAG). A total of 162 relapsed AML patients underwent either MEC or CLAG between 2005 and 2008. Baseline characteristics were similar. Median age was 55 years. Approximately 30% had a poor-risk karyotype at diagnosis and approximately 50% exhibited an intermediate-risk karyotype at diagnosis (not at relapse). Complete remission rates for CLAG and MEC were 37.9% and 23.8%, respectively (P = 0.05). The median OS of 7.3 months of CLAG bested the survival of 4.5 months for MEC (P = 0.03). Relapse-free survival showed similar effects. The 30-day early death rate was 9.4% for CLAG and 10.9% for MEC (P = 0.52). For those under 65 years of age, 36% of CLAG treated patients and 25% of MEC treated patients proceeded to allogeneic hematopoietic cell transplantation.
Sixty-eight patients underwent salvage for primary refractory disease, of which 55 had received only one prior cycle of chemotherapy. The CR rates generally mirrored relapsed patients, as CLAG achieved CR in 46% vs MEC induced CR in 22% (P = 0.09). For patients who relapsed, response rates were similar between the regimens, although a greater proportion of CLAG-treated patients (59.9%) had a short interval of first complete remission at less than 12 months compared to MEC-treated patients (45.6%) (P = 0.20).
Despite success in achieving CR in the majority of adults with AML, relapse persists as the major barrier toward long-term outcomes. Long-term survival after relapse or for refractory disease is poor, and optimal salvage therapy can not be determined based on the observational studies to date. Accordingly, the National Comprehensive Cancer Network guidelines recommend clinical trials as the preferred option. The need to maximize the chance of CR without undue toxicity may be most critical for allogeneic transplant candidates.
In this series from the Moffitt Cancer Center, the investigators catalog a recent experience of 162 patients treated over 3.5 years with either MEC (mitoxantrone, etoposide, and cytarabine) or CLAG (cladribine, high-dose cytarabine, and G-CSF). Regimens were selected based on an institutional shift from MEC to CLAG. The authors demonstrate a 37.9% response rate to CLAG compared to 23.8% after MEC (P = 0.05), which translated into a 2.8 month survival benefit (P = 0.03) of 7.3 months for CLAG as opposed to 4.5 months for MEC. CR rates and OS did not differ by regimen for patients in first relapse. Importantly in the < 65-year-old cohort, 36% of CLAG treated patients underwent allogeneic hematopoietic cell transplantation vs 25% for MEC.
Clearly, the retrospective nature of this study is the main limitation precluding more confidently assigning CLAG as the preferred therapy for salvage. Although the groups appear relatively balanced, information on molecular markers for normal karyotype AML (e.g., FLT-3 mutation) and patient health (performance status or comorbid disease) is lacking.
Since CLAG was adopted more recently, it is conceivable that improved supportive care benefitted CLAG treated patients (e.g., availability of extended spectrum azoles). The sample size does not permit well-adjusted models to interrogate specific subsets of interest. These data underscore the tremendous gap in well-conducted studies for refractory and relapsed AML.
Even if CLAG is marginally superior to MEC, as suggested by the authors, the response rates are still low and the value compared to other regimens (e.g., FLAG, clofarabine +/- cytarabine) requires further study. Most importantly, future therapy likely will target disease mechanisms as evidenced by the proliferation of clinical trials inhibiting the receptor tyrosine kinase FLT-3 rather than a "one size fits all" regimen.
In summary, CLAG showed significantly better overall response rates compared to MEC for relapsed or refractory AML in a retrospective historical comparison. Although CLAG is a reasonable therapy for salvage, treatment remains unsatisfactory and clinical trials when available should be strongly considered.
1. Fernandez HF, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 2009;361:1249-1259.
2. Breems DA, et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol 2005;23:1969-78.
3. Giles F, et al. Outcome of patients with acute myelogenous leukemia after second salvage therapy. Cancer 2005;104:547-554.